serum cystatin C levels tend to occur earlier than increases in SCr, making it possible
to detect renal insufficiency in patients at an earlier stage. This is particularly
desirable in patients with diabetes, hypertension, or cardiovascular disease who may
be at higher risk for the development of renal disease. Cystatin C is also being
evaluated as a potential predictor of cardiovascular disease, and preliminary
research has also been directed at the role of cystatin C in Alzheimer disease and
demyelinating conditions like multiple sclerosis.
Reference Range: 65–115 mg/dL or 3.6–6.3 mmol/L (fasting)
The glucose concentration in the ECF is tightly regulated by homeostatic
mechanisms to provide body tissues and cells with a ready source of energy. Two
endocrine hormones, insulin and glucagon, work synergistically to maintain normal
glucose concentrations. Insulin lowers blood glucose concentrations whereas
glucagon, along with the counterregulatory hormones epinephrine, cortisol, and
growth hormone, raises glucose levels. Because plasma glucose concentrations
fluctuate in response to ingestion of meals, most glucose concentrations are measured
in either the fasting state or the postprandial state, depending on the type of
information desired. Generally, normal glucose values refer to the plasma glucose
concentration in the fasting state. The specific laboratory assay of blood sugar
determinations must also be considered because different assay methods vary in their
specificity and sensitivity to glucose. Glucose testing using whole blood from
capillary finger sticks is used in conjunction with blood glucose metering devices for
patients with diabetes. Whole blood measurements using these devices are typically
10% to 15% lower than corresponding plasma glucose levels.
Hgb is the oxygen-carrying component of the red blood cell (RBC). During the
functional life span of RBCs (~4 months), glucose molecules irreversibly bind to
Hgb, which results in glycosylated Hgb A1c (A1c). The concentration of A1c reflects
a patient’s average blood glucose concentration for the life span of circulating RBCs.
As a result, measurement of A1c concentrations is useful to diagnose diabetes,
monitor disease progression, and/or assess the efficacy of drug therapy. In a patient
without diabetes, about 5% of Hgb is glycosylated. To diagnose diabetes, two
confirmatory A1c ≥6.5% are needed.
17 Both fasting plasma glucose (FPG) and
postprandial glucose contribute variably to the A1c measurement. One study suggests
that the higher the A1c (>8.5%), the greater the contribution of FPG to the A1c.
such, the contribution of FPG decreases as the A1c decreases. The American
Diabetes Association suggests an A1c of 7% correlates to an estimated average
glucose (eAG) of 154 mg/dL. Estimated average glucose can be calculated using the
following equation: eAG (mg/dL) = (28.7 − A1c) − 46.7.
for every 1% reduction in A1c, the risk of microvascular complications is reduced
by 37% and the risk of acute myocardial infarction (MI) by 14%.
HYPERGLYCEMIA AND HYPOGLYCEMIA
Hyperglycemia and hypoglycemia are nonspecific signs of abnormal glucose
metabolism. Diabetes mellitus is the most common cause of hyperglycemia along
with suboptimal use of insulin and/or other antidiabetic agents, high carbohydrate
dietary intake, physical inactivity, recent illness or infection, and increased
emotional stress. Hyperglycemia may be caused or worsened by certain medications
such as corticosteroids, niacin (doses >2 g/day), thiazide and loop diuretics, protease
inhibitors, atypical antipsychotics, and 3-hydroxy-3-methylglutaryl-coenzyme A
(HMG-CoA) reductase inhibitors (statins). Insufficient carbohydrate intake because
of a missed meal is the most common cause of hypoglycemia in a patient receiving
insulin or another hypoglycemic medication. In addition to insulin, drug-induced
hypoglycemia includes insulin secretagogues, fluoroquinolone antibiotics, and select
Why is the laboratory average different?
T.C. should not be alarmed with the difference in these values. His blood glucose
monitor is likely working properly and adequately measuring his plasma glucose
concentrations. However, the monitor may be reflecting a lower average glucose
concentration because of the timing of his daily testing for glucose. For example,
measuring blood glucose in a fasting state more frequently than after mealtime could
contribute to lower average concentrations because fasting values are typically lower
than postprandial concentrations. The A1c is more indicative of his average blood
sugar control during the past 90 days than the 90-day average recorded by his blood
Please refer to Chapter 53, Diabetes Mellitus, for more detailed information
regarding glucose and Hgb A1c.
Reference Range: 280–300 mOsm/kg or mmol/kg
The osmolality of a solution is a measure of the number of osmotically active ions
(i.e., particles present) per unit of solution. It is the total number of particles in the
solution, not the weight of the particle or the nature of the particle that determines
osmolality. Because 1 mole of a substance contains 6 × 10
concentrations of all substances in the undissociated state exert the same osmotic
pressure. A mole of an ionized compound such as Na
particles in solution as 1 mole of an undissociated compound such as glucose. In
most situations, the primary determinants of serum osmolality in the ECF are sodium
(and its accompanying anions), glucose, and BUN. If one corrects for the
concentrations of glucose and BUN, the serum concentration of sodium closely
mirrors the serum osmolality. A useful formula (Eq. 2-8) is as follows:
Serum osmolality is helpful when evaluating fluid and electrolyte disorders,
particularly sodium imbalances. The difference between the measured serum
osmolality and the calculated serum osmolality is commonly referred to as the
“osmol gap.” Please note that in practice, osmolality and osmolarity are often used
interchangeably. The reader is referred to Chapter 27, Fluid and Electrolyte
Disorders, for a more detailed discussion of osmolality.
Frequently, multiple laboratory tests are needed for a given patient. Common clinical
laboratory panels include a basic metabolic panel (BMP), comprehensive metabolic
panel, electrolyte, hepatic function, and renal function panels (Table 2-4). Clinicians
will often use the following abbreviated method to report a BMP in written medical
Laboratory Panels Electrolyte BMP CMP Hepatic Renal
Alkaline phosphatase (ALP) ✓ ✓
Alanine aminotransferase (ALT,
glutamic:oxaloacetic transaminase; SGPT, serum glutamic:pyruvic transaminase.
Multichemistry tests have become routinely used because they quickly provide
basic information concerning organ function at relatively low cost. In addition,
laboratory automation frequently makes it more cost effective to order a battery of
tests within a panel versus a single test. A potential disadvantage of obtaining a
battery of tests, however, is that clinicians may be inclined to pursue further
laboratory testing when “abnormalities” are not clinically relevant. It is important to
note that the individual laboratory tests included in a particular multichemistry panel
may vary among clinical laboratories.
Reference Range: 8.6–10.3 mg/dL or 2.2–2.74 mmol/L
Calcium has two key physiologic functions within our body; it is an essential
intracellular messenger in cells and tissues and a key component of hydroxyapatite,
which provides strength, rigidity, and elasticity to the skeleton. All calcium in the
body resides primarily in the skeleton, with only about 1% freely exchangeable with
that in the ECF. This reservoir of calcium in bones maintains the concentration of
calcium in the plasma constant despite pronounced changes in the external balance of
calcium. If the homeostatic factors (i.e., parathyroid hormone, vitamin D, and
calcitonin) that regulate the calcium content of body fluid are intact, a patient can lose
25% to 30% of total body calcium without a change in the concentration of calcium
About 40% of the calcium in the ECF is bound to plasma proteins (especially
albumin); 5% to 15% is complexed with phosphate and citrate; and about 45% to
55% is in the unbound, ionized form. Most laboratories measure the total calcium
concentration; however, it is the free, ionized calcium concentration that is important
and closely regulated physiologically. Most laboratories are also able to measure the
ionized form of calcium, which has a reference range of 4.5 to 5.6 mg/dL (1.13–1.4
mmol/L). It is important to obtain an albumin level in patients in order to calculate a
corrected calcium level that would account for hypoalbuminemia.
abuse × 20 years, and hypertension. P.M’s laboratory tests revealed the following:
Alkaline phosphatase: 240 units/L
Would P.M. be considered hypocalcemic, and how should he be managed?
This case presentation provides insufficient patient data to make a conclusion
concerning treatment. However, it does illustrate the importance of treating the
patient as a whole, not as a specific laboratory value. Because calcium in the serum
is partially bound to plasma proteins (mostly albumin), the serum calcium
concentration is affected by the concentration of these plasma proteins. If the albumin
concentration is low, the reported serum calcium will generally be less than the
lower limit of normal. A useful method to estimate a corrected value for serum
calcium in the presence of a low serum albumin is to use the following guideline: the
total serum calcium will decrease by 0.8 mg/dL for each decrease of 1.0 g/dL in
serum albumin concentration. Thus, evaluating P.M.’s corrected calcium is indicated:
(4 − albuminpatient × 0.8) + calcium = corrected calcium. For P.M., his “corrected”
serum calcium is 8.4 mg/dL, which is just below the reference range and probably
does not warrant treatment with calcium supplementation unless his serum calcium
continues to decline. Direct measurement of ionized calcium is independent of
albumin concentration, making it unnecessary to correct calcium concentrations in the
Unfortunately, some clinical laboratories do not have the capability of measuring
Reference Range: 1.3–2.2 mEq/L or 0.65–1.1 mmol/L
Magnesium is primarily an intracellular electrolyte principally stored in bone and,
together with potassium and calcium, helps maintain a neutral charge within the cell.
Magnesium also serves an important metabolic role in the phosphorylation of
adenosine triphosphate (ATP). Magnesium is necessary for the formation of bone and
teeth and for normal nerve and muscle function.
A primary cause of hypomagnesemia is malnourishment. Some other factors
associated with hypomagnesemia are use of proton pump inhibitors, chronic diarrhea,
alcoholism, and diuretic use. Toxemia in pregnancy is associated with
hypomagnesemia. Hypomagnesemia needs to be corrected before attempting to
correct hypokalemia or hypocalcemia. Attempts to replace potassium or calcium in
patients with hypomagnesemia will be ineffective until the low magnesium
concentrations are adequately addressed. Excessive ingestion of magnesium-
containing antacids can lead to hypermagnesemia. Increased concentrations of
magnesium are also observed in patients with reduced renal function.
Hypermagnesemia can slow conduction in the heart, prolong PT intervals, and widen
Reference Range: 2.5–5 mg/dL or 0.80–1.6 mmol/L
The extracellular concentration of phosphate as inorganic phosphorus is the prime
determinant of the intracellular concentration, which in turn is the source of
phosphate for ATP and phospholipid synthesis. Intracellular phosphate is also
important in the regulation of nucleotide degradation.
The ECF concentration of phosphate is influenced by parathyroid hormone,
intestinal phosphate absorption, renal function, bone metabolism, and nutrition.
Moderate hypophosphatemia is encountered by malnourished patients (especially
patients. Clinical consequences of severe hypophosphatemia involve nervous system
dysfunction, muscle weakness, rhabdomyolysis, cardiac irregularities, and
dysfunction of leukocytes and erythrocytes. Hyperphosphatemia is most commonly
caused by renal insufficiency, although increased vitamin D, hypoparathyroidism, and
advanced malignancies are also significant causes.
Reference Range: 3–8 mg/dL or 179–476 µmol/L
Uric acid is an end product of the metabolic breakdown of purines. It is commonly
referred to as a metabolically inert compound offering little biologic role. The renal
system is responsible for 60% to 70% of total body uric acid excretion. Most uric
acid is freely filtered with approximately 90% reabsorbed via the nephron.
Increased serum uric acid concentrations can result from either a decrease in urate
excretion (e.g., renal dysfunction) or excessive urate production (e.g., increased
purine metabolism resulting from cytotoxic therapy of neoplastic or
myeloproliferative disorders). Gout, a common arthritic condition characterized by
hyperuricemia, is usually associated with increased serum concentrations of uric acid
along with deposits of monosodium urate crystals in joints. Low serum uric acid
concentrations are inconsequential and are usually reflective of drugs that have
hypouricemic activity (e.g., high dosages of salicylates).
Reference Range: 19.5–35.8 mg/dL or 195–358 mg/L
Prealbumin is an important serum protein, but in comparison with other proteins, it
accounts for a relatively small percentage of all circulating proteins. It is also
referred to as thyroxine-binding prealbumin owing to its role as a transport
mechanism for triiodothyronine (T3
frequently used to monitor patients at risk for poor nutrition (e.g., patients with eating
disorders, patients with human immunodeficiency virus, or patients receiving total
parenteral nutrition). Compared with the long half-life of albumin (about 3 weeks),
the half-life of prealbumin is only 1 to 2 days. This shorter half-life provides a more
accurate reflection of acute changes in protein synthesis, catabolism, and ultimately
immediate nutrition status. Hepatic disease and malnutrition are associated with
decreases in prealbumin (and albumin). Hodgkin lymphoma, pregnancy, chronic
kidney disease, and corticosteroid use can increase prealbumin serum concentrations.
Reference Range: 3.6–5 g/dL or 36–50 g/L
Albumin, produced by the liver, contributes approximately 80% to serum colloid
osmotic pressure. As a result, hypoalbuminemic states are commonly associated with
edema and third spacing of ECF. A lack of essential amino acids from malnutrition or
malabsorption, or impaired albumin synthesis by the liver, can result in decreased
serum albumin concentrations. Most forms of hepatic insufficiency are associated
with decreased synthesis of albumin. It can be lost directly from the blood because of
hemorrhage, burns, or exudates or it may be lost directly into the urine because of
nephrosis. Serum albumin concentrations seldom increase, but increases may be
noted in volume depletion, in shock, or immediately after the administration of large
amounts of intravenous albumin. In addition to its diagnostic value, albumin
concentration is an important consideration in the therapeutic monitoring of drugs and
electrolytes that are highly protein bound (e.g., phenytoin, digoxin, and calcium). In
cases of severe hypoalbuminemia, determination of the “free” or unbound
concentration of these entities might be necessary for an accurate assessment of drug
Reference Range: 2.3–3.5 g/dL or 23–35 g/L
In addition to albumin, globulin is another primary plasma protein. Whereas
albumin principally functions to maintain serum oncotic pressure, globulins play an
active role in immunologic processes. The globulins can be separated into several
subgroups such as α, β, and γ. The γ-globulins can be separated further into various
immunoglobulins (e.g., IgA, IgM, and IgG). Chronic infection or rheumatoid arthritis
can increase immunoglobulin levels, and fractionation of immunoglobulins can
provide useful information in the evaluation of immune disorders. Because globulin
is not manufactured solely by the liver, the ratio of albumin to globulin (the A/G
ratio) is changed in patients with liver disease. Changes in this ratio result from
decreased albumin concentration and a compensatory increase in globulin
Cardiac biomarkers are useful for the evaluation, diagnosis, and monitoring of
patients with suspected heart damage. These
markers, which include some enzymes, are often released into the blood when the
myocardium becomes damaged or dies. Enzyme activity is typically expressed in
terms of international units, where 1 international unit (IU) is the enzyme amount
needed to catalyze the conversion of 1 μmol of substrate per minute. The analogous
expression in SI terms involves the term katal (kat). One katal is the amount of
enzyme to catalyze 1 mole of substrate per second, making 1.0 μkat the amount for
1.0 μmol/second. Based on this information, the conversion between μkat and IU is 1
Reference Range: Female 20–170 IU/L or 0.33–2.83 µkat/L; Male 30–220 IU/L
Creatine kinase (CK), formerly known as creatine phosphokinase, catalyzes the
transfer of high-energy phosphate groups in tissues that consume large amounts of
energy (e.g., skeletal muscle, myocardium, and brain). The serum concentration of
rhabdomyolysis, or high doses of certain HMG-CoA reductase inhibitors.
CK is composed of M and B subunits, which are further divided into three
isoenzymes: MM, BB, and MB. The CK-MM isoenzyme is found predominantly in
skeletal muscle, the CK-BB is predominantly in the brain, and the CK-MB is
predominantly in the myocardium. Myocardial CK activity consists of 80% to 85%
CK-MM and 15% to 20% CK-MB. Noncardiac tissues that contain large amounts of
CK have either CK-MM or CK-BB. The MB fraction is rare in tissues other than the
myocardium, making it a more specific cardiac marker.
CK-MB typically begins to increase 3 to 6 hours after an acute MI, peaks at 12 to
24 hours, and accounts for about 5% or more of the total CK.
appears to correlate with the amount of CK-MB released into the serum (i.e., the
higher the amount of CK-MB, the more extensive the myocardial injury). Although
CK-MB levels greater than 25 units/Lare usually associated with an MI, the absolute
amount can vary, depending on the assay method.
Analysis of CK-MB provides a rapid, sensitive, specific, cost-effective, and
definitive means of detecting MI.
Reference Range: Cardiac Troponin T (cTnT) 0–0.01 ng/mL or mcg/L; Cardiac
Troponin I (cTnI) 0.04 ng/mL or mcg/L
Troponins are proteins that regulate the calcium-mediated interaction of actin and
myosin within muscles. There are two cardiac-specific troponins, cardiac troponin I
(cTnI) and cardiac troponin T (cTnT). Whereas cTnT is present in cardiac and
skeletal muscle cells, cTnI is present only in cardiac muscle.
detection of CK-MB, the presence of troponin I is a more sensitive and specific
indicator of myocardial necrosis.
25 The concentration of cTnI increases within 2 to 4
hours of an acute MI, enabling clinicians to quickly initiate appropriate therapy.
Troponin also remains elevated for about 10 days compared with the 2- to 3-day
elevation typically observed with CK-MB. cTnI levels >0.04 ng/mL are suggestive
of acute myocardial tissue necrosis, but this value may vary slightly by assay
(because of lack of standardization) and by institution. The reader is referred to
Chapter 13, Acute Coronary Syndrome, for a more detailed discussion of the use of
including elevated cTnI, supporting an acute MI?
Although CK and CK-MB are very helpful laboratory values for identifying and
assessing myocardial damage/necrosis, the utility of these values alone can be quite
limited. Troponin levels are very sensitive and specific to myocardial cell death and
can become positive sooner than CK and CK-MB and will remain elevated for a
much longer time frame (up to 10 days). So even if the CK and CK-MB are not
elevated, the troponin can pick up even the smallest amount of myocardial cell death.
Based on the clinical picture and the elevated troponin, the patient would be
classified as having a non–ST segment-elevation MI.
Reference Range: Female 12–76 mcg/L; Male 19–92 mcg/L
Myoglobin, a protein in heart and skeletal muscle cells, provides oxygen to
working muscles. Damaged muscle releases myoglobin into the bloodstream. As a
cardiac biomarker, myoglobin concentrations in serum rise within 3 hours of insult to
the myocardial tissue, peak in about 8 to 12 hours, and return to normal in about a
day. Because myoglobin serum concentrations rise more quickly than CK-MB after
myocardial injury, they can be of value in helping rule out MI in the emergency
department. Myoglobin serum concentrations, however, tend to be less specific for
myocardial tissue compared with CK-MB and troponin; trauma or ischemic injury to
noncardiac tissue can also increase serum myoglobin.
Patients with deficiencies in folate, vitamin B6
elevated serum levels of homocysteine. Homocysteine is believed to have a
destructive effect on vascular epithelium. With time, patients with elevated
homocysteine levels (>12 μmol/L) are believed to be at increased risk for cardiac
26 Screening individuals with a positive family history for elevated
homocysteine or those with premature atherosclerosis without typical risk factors has
been advocated. Understanding the association between increased homocysteine
levels and specific vitamin deficiencies, supplementation of folate, vitamin B6
vitamin B12 has been used clinically. However, data are too limited to suggest that
this approach reduces the incidence of acute MI or stroke.
Reference Range: 100–250 IU/L (adult) or 1.67–4.17 µkat/L
The enzyme lactate dehydrogenase (LDH) is present in the heart, kidney, liver, and
skeletal muscle. It is also abundantly present in erythrocytes and lung tissue. Because
increased serum concentrations of LDH can be associated with diseases in many
different organs and tissues, the diagnostic usefulness of
an LDH determination is somewhat limited. There are, however, five isoenzymes
of LDH. Although most tissues contain all five isoenzymes, some tissues have a
predominance of one of the isoenzymes. LDH1 and, to a lesser extent, LDH2
predominate in the heart. Skeletal muscle and the liver have a predominance of
. LDH3 and LDH4 are found in a variety of tissues, including the lungs, RBCs,
kidneys, brain, and pancreas. Consequently, identifying specific isoenzymes can
increase the diagnostic usefulness of serum LDH determinations.
Reference Range: <100 pg/mL or <100 ng/L: >500 pg/mL or >500 ng/L is
Brain natriuretic peptide (BNP) is released from the ventricles because of
increased myocardial demand. Elevations in BNP are indicative of patients with
CHF and volume overload. In an effort to reduce workload on the heart, BNP
counteracts the renin–angiotensin–aldosterone system and causes vasodilatory
effects, along with natriuresis (increased excretion of sodium), all geared at reducing
blood volume. Patients with some degree of CHF typically have BNP levels greater
than 100 ng/L. BNP levels greater than 500 ng/L represent definite CHF, but further
evaluation is warranted to more fully characterize the extent of impaired cardiac
27 More recently, N-terminal proBNP (NT-proBNP), a by-product from the
cleaving of pro-BNP to form BNP, is also being used in the clinical setting. BNP has
also been used as a tool for patients presenting to the emergency department with
severe dyspnea; however, studies have not demonstrated additional benefits
associated with using BNP to guide therapy or to use BNP as a criterion for
admission. The reader is referred to Chapter 14, Heart Failure, for a more detailed
Reference Range: 0–1.6 mg/dL or 0–16 mg/L
C-reactive protein (CRP) is a nonspecific, acute-phase reactant helpful in the
diagnosis and monitoring of inflammatory processes (e.g., rheumatoid arthritis and
bacterial infections). CRP is produced by the liver in response to inflammation.
Although an elevation in CRP indicates the presence of an acute inflammatory event,
the nonspecific nature of the test does little to identify the cause or location of the
inflammation. CRP is similar to an older test, the erythrocyte sedimentation rate
(ESR), but it tends to be more sensitive than ESR and is also associated with a more
rapid and greater response to acute inflammation. A potential use of CRP is as a
novel risk factor for cardiovascular disease.
28 A more sensitive test for CRP is now
available and is referred to as hs-CRP or high-sensitivity CRP. The hs-CRP test
measures the same acute-phase reactant, but it is able to detect much lower levels of
CRP, making it useful for early detection of patients at risk of cardiovascular
diseases. Cardiovascular risk assessment is stratified based on the following
criteria: patients with hs-CRP values less than 1.0 mg/L have a low risk; patients
with an hs-CRP between 1.0 and 3.0 mg/L have an average risk; and patients with an
hs-CRP greater than 3.0 mg/L are considered to be at high risk. It is important to
realize that although hs-CRP is a new indicator for cardiovascular disease risk,
evaluation of other well-established patient risk factors are still the gold standard
and must be taken into consideration to determine the patient’s overall risk of
cardiovascular disease. CRP has also been used to assess chronic inflammatory
diseases such as rheumatoid arthritis and Crohn disease. Additionally, because viral
infections do not typically increase CRP serum concentrations, the use of CRP as a
diagnostic tool to differentiate viral from bacterial infections might be clinically
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